This invention relates to compositions for inhibiting the fertility of female mammals wherein the fertility is initiated and characterized by deposit of semen in the vaginal cavity with subsequent transport into the genital tract. While the invention is applicable to all female mammals having this fertility characteristic, it has particular application to inhibiting the fertility of a human female.
The science of fertility inhibition and control has advanced rapidly in recent years such that the clinical efficacy of certain pharmaceutical products has become well established. In addition to orally administered products, containing one or more hormonal substances such as progestational substances and/or estrogenic substances and mechanical devices, there has recently been developed "slow release" methods of administering such products, as by the implantation in the uterine cavity of a plastic capsule containing the fertility control substance. U.S. Pat. Nos. 3,545,439 to Duncan and 3,572,335 to Robinson; Cohen, et al., "The Effects of An Intracervical Steroid-Releasing Device on the Cervical Mucus", Fertility and Sterility, Volume 21, No. 10, October 1970. A general review of the state-of-the-art of fertility control is given in Birth Control Contraception and Abortion, by Rudel, et al., The MacMillan Company, New York.
The methods of fertility inhibition to date, however, are based upon the systemic absorption of the fertility control agent, requiring large single doses or large cumulative amounts of the agent. This often results in adverse side effects. For example, it has been reported that anti-fertility preparations containing estrogen are significantly related to the occurrence of certain thromboembolic diseases such as blood clotting. Such anti-fertility preparations have also been linked to diabetes and cancer, as well as to relatively minor, but bothersome, side effects such as nausea, weight gain and nervousness. Even in those developments in which estrogenic hormones have been totally eliminated from the preparations, the mode of application is systemic, as by oral administration, which still results in more or less serious side effects both known and unknown.
A high level of efficacy in conjunction with low cost and elimination of injurious or seriously discomforting side effects are the primary requisites in an anti-fertility preparation or fertility control method. However, the development of a new fertility control product requires complex and long-term clinical trials for Government approval before the efficacy and side effects are adjudged acceptable for public use. Accordingly, a fertility-control composition and method which would minimize governmentally-required clinical trials and the like, while satisfying the other requisites, could quickly be made publicly available.
It has also been reported that certain fertility control preparations, known for their efficacy by oral administration or by surgical implantation into the uterine cavity, have some local effect on the cervical musus secretions. In particular, it is known that certain estrogenic substances cause cervical secretions which are profuse, watery, clear, alkaline and favorable for sperm penetration, and that the administration of certain progestational agents result in cervical secretions which are reduced in volume, are scanty, fixed, opaque, less alkaline or acid, contain an increased number of leukocytes, and are unfavorable for sperm penetration. The former condition of the cervical secretions are also associated with the preovulatory phase of the menstrual cycle when estrogen hormone production is at a relatively high rate, while the latter condition of the cervical secretions are associated with the postovulatory phase when production of the progesterone hormone is at a relatively high rate. In a normal or average 28-day menstrual cycle, estrogen secretion from a single follicle generally begins on the fifth day of the cycle with the beginning of the ripening of an egg in the follicle in an ovary. Progesterone production generally begins on the fourteenth day when the ripened egg bursts from the ovary to begin its 61/2 day trip down the Fallopian tube to the uterus. It is also known from Schumacher, "Bio-Chemistry of Cervical Mucus", Fertility and Sterility, Volume 21, No. 10, October 1970. pp 697-705 that cervical mucus secretions having the latter characteristics represent a mechanical and bio-chemical barrier against introducing organisms such as sperms, the sperms negotiating the cervical mucus barrier only when the viscosity and other characteristics of the mucus have been sufficiently reduced. The changes in cervical mucus characteristics during a normal 28-day menstrual cycle are shown schematically in FIG. 3.13 on page 120 of the Rudel, et al. text mentioned above.
Rudel, et al. also show, at pages 104-105 (FIG. 3.8) that, at low dosage, progestogen can be taken to suppress fertility without inhibiting either endometrial development or ovulation. However, to be statistically effective in preventing fertilization in the typical female, the effective progestogen dosage is that which will suppress ovulation and endometrial development in a substantial proportion of the female population.
It is also reported by Rudel, et al. at page 106 that the progestational and antiovulatory activity of different progestogens does not always follow the same order of activity. Thus, for certain progestogens, such as norethindrone and norethindrone acetate, the effective dose for inhibiting ovulation is significantly less than the dose which will produce endometrial secretory response and generally somewhat less than the dose which will produce a thermogenic, i.e., hypothalmic effect. On the other hand, for chlormadinone acetate, the ovulation inhibitory dose is generally higher than the dose for producing secretory effects. The effective dose in mg needed to produce several progestation effects in the human is shown in the following table:
______________________________________ Thermogenic Secretory Effects Ovulation Compound Effects (Hypothalamic) Inhibition ______________________________________ Norethindrone 10 0.5 0.4-0.5 Norethindrone acetate 5-10 2-4* 2.5* Chlormadinone acetate 1-2 4 2-4 ______________________________________ *Data not available for lower doses (Taken from Rudel, et al., Table 3.4 at p. 106)
The daily dose of various progestogens needed to hihibit ovulation in women (dosing from cycle days 5 to 24) is shown in the following table:
______________________________________ Inhibitory Compound Dose (mg) Assay Used ______________________________________ Chlormadinone acetate 2-4 Fertility; urinary pregnanediol and estrogens Ethynodiol diacetate 2 LH determination Lynestrol 5 LH determination; urinary pregnanediol Norgestrel 0.5 LH determination; urinary pregnanediol Norethindrone 0.4 Fertility; LH and progesterone in plasma; urinary pregnanediol and estrogens Norethindrone acetate 2 or Total gonadotropins and less pregnanediol in urine Norethynodrel 2.5 Pregnanediol excretion ______________________________________ (Taken from Rudel, et al., Table 3.5 at p. 107)
Rudel, et al. also report on specific studies on the progestational compounds chlormadinone acetate and norethindrone with respect to cervical mucus. These results which are reported in Table 3.12 at page 121 and Table 3.13 at page 122 are reproduced below.
__________________________________________________________________________ Daily No. of Dose Amount Transparency Viscosity Spinnbarkheit Ferning Patients (mg) Normal Decrease Transparent Opaque Normal Increase Normal Decrease Normal Decrease __________________________________________________________________________ 10 0.05 3 7 5 5 5 5 8 2 7 3 6 0.1 2 4 4 2 2 2 3 3 3 3 9 0.2 1 8 3 6 2 7 3 6 4 5 10 0.3 0 10 1 9 2 8 3 7 4 6 10 0.4 0 10 0 10 0 10 0 10 3 7 10 0.5 0 10 0 10 0 10 0 10 2 8 __________________________________________________________________________ From MartinexManautou, J.; GinerVelazquez, J.; and Rudel, H. W.; "Continuous progestogen contraception: A dose relationship study with chlormadinone acetate", Fertility and Sterility, 18:57-62, 1967.
______________________________________ Percentage Dose No. of Response (mg) Patients Neg. Poor Reg. Good Excellent ______________________________________ 0.1 23 0.0 43.4 21.8 21.8 13.0 0.5 115 13.1 67.0 14.8 5.1 0.0 ______________________________________ Samples of cervical mucus taken between days 9 and 16 of menstrual cycle and examined for spermatozoal motility.
Kincl, et. al. Steroids, 8(1): 5-11, July, 1966, "Inhibition of Ovulation in the Adult Estrus Rabbit by Vaginal Deposition", show the administration by intravaginal deposition of progestational compounds to achieve an anti-ovulatory activity. It is very clear that systemic absorption is intended and obtained and that without systemic absorption, the effect described by Kincl, et al. would not take place.
Greenblatt, J., Clin. Endocrin., 14: 1564-1567, December, 1954, "The Physiological Effectiveness of Progesterone Vaginal Suppositories", describes progesterone administered in the form of vaginal suppositories; the progesterone is absorbed and is clinically effective to produce systemic effects. The point of the Greenblatt disclosure is to show how systemic absorption is as effective as oral administration in obtaining such systemic effects to provide an anti-fertility result. Clearly, Greenblatt never contemplated a topical application which would provide a non-systemic effect only.
Ringler, Steroids, 7(4): 341-349, April, 1966, "Efficacy of Topically Applied Progestational Agents", and Shipley, Steroids, 5(5): 699-717, May, 1965, "Effectiveness of Topical Application of a Number of Progestins", are similar in that both show the use of progestational steroids which are absorbed after topical application to rabbits to obtain a systemically generated anti-fertility effect. Again, systemic rather than non-systemic results are desired and obtained and in this case the topical application is only carried out as a means of applying the agent systemically. Non-systemic effects producing anti-fertility results were not contemplated by Ringler or Shipley.
Irish Pat. No. 1173/65 is similar in that it shows the topical application of a progestational agent carried in a suitable carrier such as a foam to achieve an anti-fertility effect. However, once again, the effect produced is systemic and is intended to be systemic. The reference does not suggest a non-systemic effect without, also, a systemic effect.
Nevertheless, so far as is known, there have been no known techniques for providing effective contact of the progestational compound with the cervical tissues in a self-administrable form while avoiding undesirable side effects of fertility inhibition, due principally to systemic absorption of the active ingredient.